A small study in 18 patients assessing the effectiveness of the drug losartan for treating Marfan syndrome in children has yielded encouraging results. Johns Hopkins researchers showed that losartan-a compound used for years to treat high blood pressure-slowed the enlargement of the aorta, the most life-threatening defect associated with Marfan syndrome. Results of their findings were reported in the June 26, 2008 edition off the New England Journal of Medicine.

“This experience increases my belief that losartan holds great promise for treating Marfan syndrome,” says Harry Dietz, M.D., a professor in the McKusick-Nathans Institute of Genetic Medicine and director of the William S. Smilow Center for Marfan Syndrome Research at Hopkins. “This would be the first therapy generated by basic research that revealed the molecular mechanism of this genetic disease.”

In mice engineered to contain the same genetic defect that causes Marfan syndrome, Dietz’s team previously discovered that most features of the syndrome arise from excessive activity of the protein TGF-beta, a protein vital to cell growth and specialization.

Treating the mice with losartan, a drug also known to decrease TGF-beta activity, slowed, and in some cases stopped, potentially lethal enlargement of the aorta, the body’s largest. Such enlargement is a key feature of Marfan syndrome.

On the basis of these findings, the Pediatric Heart Network of the National Heart, Lung and Blood Institute at the National Institutes of Health has approved and launched a large, multicenter clinical trial of losartan for Marfan syndrome, which Dietz oversees with Ronald Lacro, M.D., director of the cardiovascular genetics clinic at Children’s Hospital Boston.

Before the start of that clinical trial, physicians at Johns Hopkins felt compelled to first try losartan in a small group of children, with severe Marfan syndrome, whose aortas, which carry oxygenated blood from the hear to the resto of the body, were enlarging rapidly and unresponsive to other treatment.

“These patients had severe forms of the disease and had shown progressive aortic enlargement despite treatment with existing therapies, including beta-blockers and ACE inhibitors,” says Benjamin Brooke, M.D., a research fellow in genetic medicine and surgery at Hopkins.

For the 18 patients in the small, preliminary study, the average rate of aortic enlargement before starting losartan was 3.5 millimeters in diameter per year, and after losartan treatment, just shy of a half millimeter per year. “While the response to therapy varied somewhat, it was exciting to see such a dramatic change in the majority of these patients,” Brooke says.

“I am very encouraged by this initial experience, but it cannot substitute for a properly controlled clinical trial,” says Dietz. “I encourage patients and families with Marfan syndrome to talk to their doctors and get involved with the current clinical trial.”

The research was funded by the National Institutes of Health, Howard Hughes Medical Institute, William S. Smilow Center for Marfan Syndrome Research, Dana and Albert “Cubby” Broccoli Center for Aortic Diseases, and the National Marfan Foundation.

Authors on the paper are Brooke, Dietz, Jennifer Habashi, Daniel Judge, Bart Loeys and Nishant Patel, all of Hopkins.

About Marfan Syndrome

Marfan syndrome is a heritable condition that affects the connective tissue. The primary purpose of connective tissue is to hold the body together and provide a framework for growth and development. In Marfan syndrome, the connective tissue is defective and does not act as it should. Because connective tissue is found throughout the body, Marfan syndrome can affect many body systems, including the skeleton, eyes, heart and blood vessels, nervous system, skin, and lungs.

Marfan syndrome is caused by a defect (mutation) in the gene that determines the structure of fibrillin, a protein that is an important part of connective tissue. A person with Marfan syndrome is born with the disorder, even though it may not be diagnosed until later in life.

Risk Factors 

Marfan syndrome affects men, women, and children, and has been found among people of all races and ethnic backgrounds. It is estimated that at least 1 in 5,000 people in the United States have the disorder. The defective gene can be inherited: The child of a person who has Marfan syndrome has a 50 percent chance of inheriting the disease. Sometimes a new gene defect occurs during the formation of sperm or egg cells, but two unaffected parents have only a 1 in 10,000 chance of having a child with Marfan syndrome. Possibly 25 percent of cases are due to a spontaneous mutation at the time of conception.

Marfan Syndrome Symptoms

Marfan Syndrome affects different people in different ways. Some people have only mild symptoms, while others are more severely affected. In most cases, the symptoms progress as the person ages. The body systems most often affected by Marfan syndrome are:

• Skeleton--Since Marfan syndrome affects the long bones of the skeleton, arms, legs, fingers, and toes may be disproportionately long in relation to the rest of the body. A person with Marfan syndrome often has a long, narrow face, and the roof of the mouth may be arched, causing the teeth to be crowded. Other skeletal abnormalities include a sternum (breastbone) that is either protruding or indented, curvature of the spine (scoliosis), and flat feet.
• Eyes--More than half of all people with Marfan syndrome experience dislocation of one or both lenses of the eye. The lens may be slightly higher or lower than normal and may be shifted off to one side. The dislocation may be minimal, or it may be pronounced and obvious.Many people with Marfan syndrome are also nearsighted (myopic), and some can develop early glaucoma (high pressure within the eye) or cataracts (the eye's lens loses its clearness).  Retinal detachment is a possible serious complication of this disorder.
• Skin--Many people with Marfan syndrome develop stretch marks on their skin, even without any weight change. These stretch marks can occur at any age and pose no health risk. However, people with Marfan syndrome are also at increased risk for developing an abdominal or inguinal hernia where a bulge develops that contains part of the intestines.
• Lungs--Although connective tissue abnormalities make the tiny air sacs within the lungs less elastic, people with Marfan syndrome generally do not experience noticeable problems with their lungs. If, however, these tiny air sacs become stretched or swollen, the risk of lung collapse may increase. Rarely, people with Marfan syndrome may have sleep-related breathing disorders such as snoring or sleep apnea (a sleep disorder characterized by brief periods when breathing stops).
• Nervous system--The brain and spinal cord are surrounded by fluid contained by a membrane called the dura, which is composed of connective tissue. As people with Marfan syndrome get older, the dura often weakens and stretches, then begins to weigh on the vertebrae in the lower spine and wear away the bone surrounding the spinal cord. This is called dural ectasia. These changes may cause only mild discomfort or may lead to radiated pain in the abdomen or to pain, numbness, or weakness of the legs.
• Heart and blood vessels (cardiovascular system)--Most people with Marfan syndrome have abnormalities associated with the heart and blood vessels which may cause serious heart problems or sometimes sudden death.